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Title: Mutations in KEOPS-complex genes cause nephritic syndrome with primary microcephaly
Authors: Daniela A. Braun
Jia Rao
Geraldine Mollet
David Schapiro
Marie Claire Daugeron
Weizhen Tan
Olivier Gribouval
Olivia Boyer
Patrick Revy
Tilman Jobst-Schwan
Johanna Magdalena Schmidt
Jennifer A. Lawson
Denny Schanze
Shazia Ashraf
Jeremy F.P. Ullmann
Charlotte A. Hoogstraten
Nathalie Boddaert
Bruno Collinet
Gaelle Martin
Dominique Liger
Svjetlana Lovric
Monica Furlano
I. Chiara Guerrera
Oraly Sanchez-Ferras
Jennifer F. Hu
Anne Claire Boschat
Sylvia Sanquer
Björn Menten
Sarah Vergult
Nina De Rocker
Merlin Airik
Tobias Hermle
Shirlee Shril
Eugen Widmeier
Heon Yung Gee
Won Il Choi
Carolin E. Sadowski
Werner L. Pabst
Jillian K. Warejko
Ankana Daga
Tamara Basta
Verena Matejas
Karin Scharmann
Sandra D. Kienast
Babak Behnam
Brendan Beeson
Amber Begtrup
Malcolm Bruce
Gaik Siew Ch'Ng
Shuan Pei Lin
Jui Hsing Chang
Chao Huei Chen
Megan T. Cho
Patrick M. Gaffney
Patrick E. Gipson
Chyong Hsin Hsu
Jameela A. Kari
Yu Yuan Ke
Cathy Kiraly-Borri
Wai Ming Lai
Emmanuelle Lemyre
Rebecca Okashah Littlejohn
Amira Masri
Mastaneh Moghtaderi
Kazuyuki Nakamura
Fatih Ozaltin
Marleen Praet
Chitra Prasad
Agnieszka Prytula
Elizabeth R. Roeder
Patrick Rump
Rhonda E. Schnur
Takashi Shiihara
Manish D. Sinha
Neveen A. Soliman
Children's Hospital Boston
Universite Paris Descartes
Universite Paris-Sud XI
Hôpital Necker Enfants Malades
Medizinische Fakultät und Uniklinikum Magdeburg
Harvard Medical School
Sorbonne Universite
Universidad Autónoma de Barcelona, Facultad de Medicina
McGill University, Rosalind and Morris Goodman Cancer Research Centre
Massachusetts Institute of Technology
Imagine Institute
University Hospital of Ghent
Universität Freiburg im Breisgau
Yonsei University College of Medicine
Friedrich-Alexander-Universität Erlangen-Nürnberg
Max Planck Institut für molekulare Biomedizin
Westfälische Wilhelms-Universität Münster
Iran University of Medical Sciences
National Human Genome Research Institute
King Edward Memorial Hospital for Women
GeneDX, Inc.
Kuala Lumpur Hospital
MacKay Children's Hospital
Mackay Medical College
Veterans General Hospital-Taichung Taiwan
Oklahoma Medical Research Foundation
University of Michigan, Ann Arbor
King Abdulaziz University
Princess Margaret Hospital Hong Kong
University of Montreal
Baylor College of Medicine
The University of Jordan
Tehran University of Medical Sciences
Yamagata University Faculty of Medicine
Hacettepe University, Faculty of Medicine
Hacettepe Üniversitesi
Western University
University of Groningen, University Medical Center Groningen
Guy's and St Thomas' NHS Foundation Trust
Cairo University
Egyptian Group for Orphan Renal Diseases
Centre Hospitalier Universitaire Ibn-Rochd
Massachusetts General Hospital
Chi Mei Medical Center
Taipei Medical University
Universitäts Klinikum Essen und Medizinische Fakultät
University of Utah, School of Medicine
Mahidol University
University of Oklahoma Health Sciences Center
UT Southwestern Medical School
Tuen Mun Hospital
Singapore-MIT Alliance
Yale University School of Medicine
Rockefeller University
Hospital for Sick Children University of Toronto
Pediatric Nephrology Institute
Keywords: Biochemistry, Genetics and Molecular Biology
Issue Date: 1-Oct-2017
Citation: Nature Genetics. Vol.49, No.10 (2017), 1529-1538
Abstract: © 2017 Nature America, Inc., part of Springer Nature. All rights reserved. Galloway-Mowat syndrome (GAMOS) is an autosomalrecessive disease characterized by the combination of earlyonset nephrotic syndrome (SRNS) and microcephaly with brain anomalies. Here we identified recessive mutations in OSGEP, TP53RK, TPRKB, and LAGE3, genes encoding the four subunits of the KEOPS complex, in 37 individuals from 32 families with GAMOS. CRISPR-Cas9 knockout in zebrafish and mice recapitulated the human phenotype of primary microcephaly and resulted in early lethality. Knockdown of OSGEP, TP53RK, or TPRKB inhibited cell proliferation, which human mutations did not rescue. Furthermore, knockdown of these genes impaired protein translation, caused endoplasmic reticulum stress, activated DNA-damage-response signaling, and ultimately induced apoptosis. Knockdown of OSGEP or TP53RK induced defects in the actin cytoskeleton and decreased the migration rate of human podocytes, an established intermediate phenotype of SRNS. We thus identified four new monogenic causes of GAMOS, describe a link between KEOPS function and human disease, and delineate potential pathogenic mechanisms.
ISSN: 15461718
Appears in Collections:Scopus 2016-2017

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